Obesity enhances decrements in pulmonary function induced by exposure to ozone (O3), a common environmental pollutant. However, the mechanistic basis underlying this relationship is poorly understood. Our published data demonstrate that obese as compared to lean, wild-type mice exhibit enhanced airway responsiveness to bronchoconstrictors and increased pulmonary inflammation following exposure to O3. Obesity leads to chronic systemic inflammation, which is characterized by increased circulating levels of cytokines, chemokines, and hormones. These substances, collectively termed adipokines, are largely pro- inflammatory in nature. Thus, the presence of chronic systemic inflammation in obesity may amplify subsequent inflammatory responses, including those elicited by O3 inhalation, leading to enhanced decrements in pulmonary function. Of the pro-inflammatory adipokines increased in obesity, our preliminary data suggest that chemerin is a key mediator for the development of obesity-induced, enhanced decrements in pulmonary function induced by exposure to O3. Our preliminary data demonstrate that (1) O3-induced increases in the levels of chemerin in the bronchoalveolar lavage fluid are greater in obese as compared to lean, wild-type mice and (2) O3-induced pulmonary inflammation is reduced in wild-type mice administered a neutralizing antibody against chemerin. Data from others demonstrate that macrophages express chemerin receptor 23 (ChemR23), the only cell surface receptor for chemerin that results in robust intracellular signaling, and (2) chemerin-ChemR23 signaling can lead to the synthesis and/or release of pro-inflammatory cytokines and chemokines, relevant to O3-induced airway hyperresponsiveness (AHR) and pulmonary inflammation from a variety of cell types, including macrophages. Based on these observations, we shall test the central hypothesis that obesity exacerbates decrements in pulmonary function induced by exposure to O3 through chemerin-induced augmentation of pulmonary inflammation via ChemR23 on alveolar macrophages. We propose two Specific Aims to test this hypothesis. In Aim 1, we shall examine the role of chemerin in the development of increased airway responsiveness to methacholine and increased pulmonary inflammation induced by exposure to O3 in obese mice through the use of a neutralizing antibody against chemerin. In Aim 2, we shall examine the ability of chemerin to stimulate the release of cytokines and chemokines, which contribute to O3-induced AHR and pulmonary inflammation, from MH-S cells, an immortalized alveolar macrophage cell line in the presence or absence of small interfering RNA directed against murine ChemR23. These investigations will illuminate the importance of chemerin-ChemR23 signaling in the development of O3-induced AHR and pulmonary inflammation. These outcomes will be useful for developing preventative or palliative therapies directed at interfering with chemerin's detrimental effects on pulmonary biology, especially in the obese.